Synthesis of pseudo saccharide precursors through ‘off template site’ Michael –Wittig reaction on sugar derived enal #

[3+3] Annulation protocol at an‘off template site’ on the sugar derived enal synthon effectively resulted in the formation of C-C linked pseudo saccharide precursors. Thus, the enolate of phosphorane generated from ethyl acetoacetate first undergoes a Michael reaction on the enal followed by a Wittig reaction to furnish the target saccharides, where the chirality is very effectively translated from the parent sugar


Introduction
Several antibiotics and compounds of biological interest incorporate glycosides of pseudosugars [1][2][3] or carba-sugars 4 , since, they are endowed with relatively greater stability towards glycosidase-induced hydrolysis.Besides the application as enzyme inhibitors, the carba-sugars are discussed as synthetic intermediates for the preparation of more efficient drugs in order to substitute carbohydrate moieties 5 .Thus, development of novel and efficient methods for the enantioselective or enantiospecific construction of carbocycles 6 resulted in a variety of useful routes such as Diels-Alder approaches, the double Michael cyclisation, 1,3-dipolar cycloaddition and free radical-induced C-C bond formation.As part of our ongoing efforts on the transformation of monosaccharides into new glycosubstances [7][8][9][10][11][12][13][14][15] , herein we describe the synthesis of C-C linked pseudo saccharide precursors 1-5 (Figure 1), adopting a Michael-Wittig reaction on sugar-derived enal.

Results and Discussion
From the retro synthetic analysis of 1-5 (Scheme 1), it was envisaged that, the enones 6a-d are appropriate late stage intermediates, which could be realized from the condensation of α, βunsaturated aldehyde 7 and Wittig ylide 8 by a Michael-Wittig reaction.The enal 7 in turn could be made from D-glucose through aldehyde 9, while 8 could be prepared from ethyl acetoacetate.Aldehyde 9 16 was subjected to Wittig olefination (Scheme 2) with (ethoxycarbonyl methylene)triphenylphosphorane in benzene at reflux to give the ester 10, which on reduction with DIBAL-H in CH 2 Cl 2 afforded 11 in 86% yield.Oxidation of 11 with PDC in CH 2 Cl 2 at reflux gave enal 7 (95%), which on reaction with 8 17 in the presence of NaH and two drops of water 18 in THF at 50 0 C for 10 min., resulted in the formation of 6a-d as a partially separable mixture of diastereoisomers in (6:1.5:1.5:1)75% overall yield.The stereochemical outcome of each of the annulated products was unambiguously determined by 1 H NMR spectra.The formation of 6a as major product, in the present study, indicates that the initial Michael-addition of nucleophile (sodium enolate of 8) on the γ -alkoxy enal system 7 results in the formation of a syn product 19 and the aldehyde moiety of the adduct concomitantly undergoes a Wittig reaction in affording the cyclohexenone derivatives 6a-d.
The mixture of diastereoisomers 6a and 6b were separated from 6c and 6d by column chromatography and both the mixtures were independently treated with NaBH 4 in ethanol (Scheme 3) in the presence of CeCl 3 .7H 2 O under Luche's reaction conditions 20 .6a and 6b afforded a mixture of alcohols 12 (major), 13 (minor) and 14 (single isomer) in the ratio of 4:1:2 respectively in a combined yield of 88%, while 6c and 6d furnished 15 as an inseparable mixture of alcohols.Acetylation of alcohols 12-14 with acetic anhydride in pyridine independently gave the corresponding acetates  Stereoselective cis-hydroxylation of the olefins 16-20 was affected using OsO 4 -NMO in acetone-water (3:1) system to afford the diols 22-26.The stereochemical outcome, anti-to the -OAc group, is in accordance with literature 21 precedence.Acetylation of diols 22-26 with acetic anhydride in pyridine afforded the corresponding pseudo saccharide precursors 1-5 in quantitative yields.
The structures of 1-5 were fully confirmed with the help of detailed NMR analysis using the vicinal couplings (J) as well as the data from the NOESY experiments.For compound 1, the characteristic NOE cross peaks (Figure 2) H6-H8, H6-H10a, H8-H10a and H7-H5 and J 5,6 , J 6,7 , J 7,8 and J 5,10a values of about 10 Hz are in consensus with a chair conformation, 8 C 5 , for the carbocycle ring.Interestingly, most of the substituents in this conformation take energetically favored equatorial position.For compound 2, the structure and conformation are supported by strong NOE cross peaks between H5-H9 and H6-H10a as well as large value of about 10 Hz for J 5,6 , J 5,10a and J 9,10a whereas large NOE cross peaks between H5-H7 as well as J 5,10a 13.0 Hz and J 7,8 10.8 Hz confirm the structure of compound 3.Such a conformation for the carbocycle ring is again energetically favored, as apart from substituent at C-6 and C-9, all the substituents are placed equatorial.For compound 4 the characteristic NOE cross peaks H6-H10a and H5-H9 as well as large value of about 10 Hz for J 9, 10a and J 5, 10a and 9.8 Hz for J 5, 6 are in conformity with a chair conformation, while for 5, the structure and conformation are supported by strong NOE cross peaks between H5-H7, H8-H10a and J 5, 10a and J 7, 8 of about 10 Hz .The six membered rings in all these molecules take 8 C 5 chair conformation.The five membered ring is puckered in all the compounds.Small values of J 1,2 , J 2,3 and J 3,4 point out to a twist conformation for the sugar ring.The presence of NOE cross peaks between H1-Me (A), H2-Me (A) and H4-Me (B) implies an envelop conformation for the five membered ring containing isopropylidine group.The relative orientation of the carbocycle and sugar rings is derived with the help of NOESY experiments.For 1-3 the strong NOE cross peaks between H3-H10e, H4-H10a, and weak NOE cross peaks between H3-H10a and H4-H10e and H10e-OMe confirm the structures shown in Figure 2.For 4 and 5, on the other hand, there is change in configuration at C5 and the NOE cross peak between H3-H6 and H4-H6 support relative orientation of the rings.Molecular mechanics study is carried out on 1-5 using Sybyl 22 and the results obtained agree with the experimental data.Dihedral angle H4-C4-C5-H5 of about 170° for 1-3 and 5 (Figure 3) is consistent with large J 4,5 of about 10 Hz.For 4 the calculated dihedral angle H4-C4-C5-H5 of -129° is conformity in experimentally observed J 4,5 4.3 Hz.
These observations are in agreement with the experimental data supporting the trans stereochemistry across the rings.Thus, pseudo saccharide precursors 1-5 were synthesised by adopting an 'off template site' stereoselective [3+3] annulation approach, where the chirality of the carbocycle is induced from the sugar template.In this present [3+3] annulation protocol, Michael-Wittig reaction was exploited for the first time in carbohydrate chemistry for the installation of carbocycle ring system at C-5 of sugar synthon.Due to the ready availability of reagents and simple reaction conditions, the present protocol and the pseudo saccharide precursors 1-5 should find a wide use in the synthesis of several C-glycoside mimics towards the bioactive carbohydrates.

Experimental Section
General Procedures.Solvents were dried over standard drying agents and freshly distilled prior to use. 1 H NMR (200 MHz, 400 MHz, 500 MHz) and 13 C NMR (50 MHz, 100 MHz, 125 MHz) spectra were recorded in deuteriochloroform solution with tetramethylsilane as an internal reference on Varian Gemini-200 MHz, Unity-400 MHz and INOVA-500 MHz spectrometers and J values are given in Hz.Optical rotations were measured with a JASCO DIP-370 instrument and [α] D values are in units of 10 -1 deg cm 2 g -1 .Organic solutions were dried over anhydrous Na 2 SO 4 and concentrated below 40°C in vacuo.HRMS were recorded on V G Autospec Mass Spectrometer at 5 or 7 K resolution using perfluoro kerosene as an internal reference.Infrared (IR) are reported in wavenumbers (cm -1 ).The nomenclature mentioned in the experimental section was adopted from ACD/Name version 1.0β, ACD Inc., Toronto, Canada.

Figure 3 .
Figure 3. Structures obtained from energy minimization for 1-5.(Note: For clarity in visualization the protecting groups are not shown in the figure).
2 ) under nitrogen atmosphere for 15 min.After 3 h, methanol (15 mL) was added, stirred for 1 h and brought to room temperature.The separated solid was filtered off and washed with CH 2 Cl 2 (2 x 50 mL).The combined organic layers were washed with brine (50 mL) and dried (